BACKGROUND Kidney outcomes have been variably defined using nonstandardized composite end points in key heart failure trials, thus introducing complexity in their interpretation and cross-trial comparability. We examined the effects of steroidal mineralocorticoid receptor antagonists, the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan, and SGLT2 (sodium-glucose cotransporter-2) inhibitors on composite kidney end points using uniform definitions in 6 contemporary heart failure trials. METHODS Individual participant-level data from trials of steroidal mineralocorticoid receptor antagonists (EMPHASIS-HF [Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure], TOPCAT [Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist] Americas), angiotensin receptor-neprilysin inhibitor (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure], PARAGON-HF [Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blockers Global Outcomes in HF With Preserved Ejection Fraction]), and SGLT2 inhibitors (DAPA-HF [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure], DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure]) were included. The standardized composite kidney end point was defined as a sustained decline (a reduction in estimated glomerular filtration rate (eGFR) confirmed by a subsequent measurement at least 30 days later) in eGFR by 40%, 50%, or 57%; end-stage kidney disease; or renal death. eGFR was recalculated in a standardized manner using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS Among 28 690 participants across the 6 trials (median age, 69 years [interquartile range, 62-76]; 9656 [33.7%] women), the proportion experiencing the composite kidney end point with a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) ranged from 0.3% to 3.3%. The proportion of patients experiencing this end point with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% to 10.0%. The steroidal mineralocorticoid receptor antagonists doubled the risk of the composite kidney end point when applying the least stringent definition compared with placebo, but these effects were less apparent and no longer significant with application of more stringent definitions. Angiotensin receptor-neprilysin inhibitor appeared to consistently reduce the occurrence of the composite kidney end points irrespective of the specific eGFR threshold applied. The potential benefits of SGLT2 inhibitors on the composite kidney end points appeared more apparent when defined by more stringent eGFR thresholds, although none of these effects individually were statistically significant. CONCLUSIONS When applying standardized stringent kidney end point definitions, steroidal mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitor, and SGLT2 inhibitors have either neutral or beneficial effects on kidney outcomes in heart failure. Applying less stringent definitions increased event rates but included acute declines in eGFR that might not ultimately reflect long-term effects on kidney disease progression.

中文翻译：

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心力衰竭药物治疗对标准化肾脏结果的治疗效果：6 项随机临床试验的综合个体参与者级分析。


背景 在关键心力衰竭试验中，使用非标准化复合终点对肾脏结局进行了可变定义，因此在解释和跨试验可比性方面引入了复杂性。我们在 6 项当代心力衰竭试验中使用统一定义检查了甾体盐皮质激素受体拮抗剂、血管紧张素受体-脑啡肽酶抑制剂沙库巴曲/缬沙坦和 SGLT2 （钠-葡萄糖协同转运蛋白-2） 抑制剂对复合肾终点的影响。方法 来自甾体盐皮质激素受体拮抗剂（EMPHASIS-HF [依普利酮在轻度患者中的心力衰竭住院和生存研究]、TOPCAT [醛固酮拮抗剂治疗保留的心脏功能心力衰竭] 美洲）、血管紧张素受体-脑啡肽酶抑制剂（PARADIGM-HF [血管紧张素受体-脑啡肽酶抑制剂与 ACEI 的前瞻性比较以确定对全球死亡率和发病率的影响心力衰竭]、PARAGON-HF [血管紧张素受体-脑啡肽酶抑制剂与血管紧张素受体阻滞剂射血分数保留 HF 全球结局的前瞻性比较]）和 SGLT2 抑制剂 （DAPA-HF [达格列净和预防心力衰竭不良结局]、DELIVER [达格列净评估以改善射血分数保留心力衰竭患者的生活]）被包括在内。标准化复合肾终点定义为 eGFR 持续下降（至少 30 天后通过后续测量证实估计肾小球滤过率 （eGFR） 降低）40%、50% 或 57%;终末期肾病;或肾死亡。 使用 2009 年慢性肾脏病流行病学协作组织肌酐方程以标准化方式重新计算 eGFR。结果 在 6 项试验的 28 690 名参与者中 （中位年龄 69 岁 [四分位距，62-76];9656 名 [33.7%] 女性），经历复合肾终点的比例对肾功能持续下降有更严格的定义 （eGFR 阈值为 57%） 从 0.3% 到 3.3% 不等。经历定义不太严格的终点 （eGFR 阈值为 40%） 的患者比例为 1.0% 至 10.0%。与安慰剂相比，当应用最不严格的定义时，甾体盐皮质激素受体拮抗剂使复合肾终点的风险增加了一倍，但这些影响不太明显，并且在应用更严格的定义时不再显著。血管紧张素受体-脑啡肽酶抑制剂似乎始终减少复合肾终点的发生，而不管应用的特定 eGFR 阈值如何。当由更严格的 eGFR 阈值定义时，SGLT2 抑制剂对复合肾终点的潜在益处似乎更加明显，尽管这些影响单独没有统计学意义。结论 当应用标准化严格的肾脏终点定义时，甾体盐皮质激素受体拮抗剂、血管紧张素受体-脑啡肽酶抑制剂和 SGLT2 抑制剂对心力衰竭的肾脏结局有中性或有益的影响。应用不太严格的定义会增加事件发生率，但包括 eGFR 的急剧下降，这最终可能无法反映对肾脏疾病进展的长期影响。